# Progenitor Cells for High Endothelium in the Immune Response

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2021 · $509,659

## Abstract

PROJECT SUMMARY / ABSTRACT
High endothelial venules (HEV) are specialized post capillary portals for lymphocyte entry into lymphoid tissues
and sites of chronic inflammation from the blood. They regulate immune cell trafficking in physiologic and
pathologic settings including autoimmune diseases and cancer. HEV in lymph nodes draining sites of immune
challenge proliferate extensively to support enhanced lymphocyte recruitment, but the endothelial precursors
that give rise to high endothelium and the molecular pathways that control their proliferation and differentiation
are unclear. Our transcriptomic and immunologic studies reveal that capillary endothelial cells (CapEC) express
multiple markers classically associated with stem and progenitor cells, leading to the hypothesis that capillary
phenotype EC comprise a population of stem cell-like blood endothelial progenitors that contribute to HEV
expansion during the immune response. Under Aim 1 we will apply state-of-the-art single cell
immunofluorescence and high dimensional mass label (CyTOF) flow cytometry to uncover the diversity of EC
subsets in LN and in extra lymphoid sites of immune cell recruitment, define the kinetics and subset-specificity
of their proliferative responses to immune challenge, and reveal the time course of emergence of transitional
phenotypes leading to the amplification and maturation of functional HEV. Trajectory analyses will reveal
developmental relationships of identified subsets including identified progenitors, and immunofluorescence
histology and confocal tissue imaging will define their location within the vasculature. In Aim 2, innovative fate
mapping approaches will elucidate precursor-product relationships among BEC subsets and will define clonal
contributions of precursors to capillary and high endothelium. Aim 3 will apply transcriptional profiling of induced
EC subsets in combination with pan-EC and novel capillary EC-specific inducible gene targeting systems to
define molecular mechanisms of HEV homeostasis and pathways regulating progenitor cell activation,
amplification and contribution to HEV expansion in the immune response.
Comprehensive phenotypic analyses of blood endothelial cell subsets and their responses to immunization will
open up new areas of investigation in vascular biology and immunology. Elucidation of the mechanisms of
endothelial cell specialization and homeostasis, including mechanisms regulating endothelial cells that control
lymphocyte traffic, will lead to novel targets and approaches for the control of autoimmune inflammation and for
therapeutic regulation of immune cell traffic for vaccination and cancer immunity.

## Key facts

- **NIH application ID:** 10223152
- **Project number:** 5R01AI130471-05
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** EUGENE C BUTCHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $509,659
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223152

## Citation

> US National Institutes of Health, RePORTER application 10223152, Progenitor Cells for High Endothelium in the Immune Response (5R01AI130471-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10223152. Licensed CC0.

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